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Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 February 2002, Vol. 99, No. 3, pp. 1089-1091 BRIEF REPORT Sustained suppression of hepatitis C virus by interferon and ribavirin in hemophilic patients not responding to interferon monotherapy Elena Santagostino, Maria Grazia Rumi, Monica Rivi, Massimo Colombo, and Pier Mannuccio Mannucci for the Hepatitis Study Group of the Association of Italian Hemophilia Centers From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Division of Hepatology, IRCCS Maggiore Hospital, University of Milan, Italy.     Abstract Top Abstract Introduction Study design Results and discussion Appendix References Thirty-nine hemophiliac patients, negative for human immunodeficiency virus, with chronic hepatitis C who failed to respond to interferon (IFN) at 3 million units (MU) given subcutaneously thrice weekly for at least 3 months were retreated with 5 MU IFN for 6 months followed by 3 MU IFN in combination with daily oral doses of 1 or 1.2 g ribavirin. Thirty-four patients (87%) completed the study. In 4 patients treatment was discontinued because of treatment-related symptoms; 1 patient dropped out. Dosage reduction was required in 10 patients (26%) because of ribavirin-related anemia or IFN-related side effects. By intention-to-treat analysis, 14 (37%) had a sustained virologic response with preference for those infected by genotypes other than type 1 (43% versus 12%) and with high transaminases levels (168 U/L versus 116 U/L). Thus, IFN and ribavirin combination therapy led to a sustained suppression of hepatitis in one third of hemophiliac patients resistant to conventional monotherapy. (Blood. 2002;99:1089-1091) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion Appendix References Chronic infection with hepatitis C virus (HCV) is the leading cause of liver-related morbidity and mortality in patients with hemophilia who have received multiple transfusions.1,2 It is not clear whether the cumulative lifetime risk of cirrhosis or hepatocellular carcinoma in these patients can be attenuated by treatment with interferon  (IFN-). Hemophilic patients are frequently resistant to IFN therapy due to the long duration of HCV infection, high levels of viremia, and high prevalence of HCV genotype 1, which is an IFN-resistant virus strain.3-6 Controlled studies in nonhemophilic patients with chronic hepatitis C have demonstrated that higher rates (30%-40%) of sustained response are obtained with the administration of IFN in combination with the guanosine analogue ribavirin than with IFN monotherapy.7,8 Ribavirin is known to inhibit viral RNA polymerases in vitro,9 to increase the rate of virus mutations,10,11 to influence Th1/Th2 balance by causing a shift toward Th1 responses,12 and to suppress HCV-specific interleukin-10 (IL-10) production.13 The fact that nonhemophilic patients resistant to IFN monotherapy could achieve more sustained responses with combined administration of IFN and ribavirin14 provided the rationale for retreating all hemophilic patients refractory to IFN monotherapy with combination therapy.     Study design Top Abstract Introduction Study design Results and discussion Appendix References This multicenter open trial consisted of a treatment period of 12 months and a 6-month posttreatment follow-up period. The study was designed by the Hepatitis Study Group of the Association of Italian Hemophilia Centers, which includes all the hemophilia centers participating in the previous IFN treatment trial of naive patients.3 The study was carried out according to the international standard criteria for good clinical practice. Written informed consent was obtained from each patient. Between January and December 1998, we treated antihuman immunodeficiency virus (HIV)-negative adults (older than 18 years) with inherited bleeding disorders and chronic hepatitis C, not responding to or having a hepatitis relapse after treatment with 3 million units (MU) IFN given thrice weekly for a minimum of 3 months. Patients were included in the study after a 6-month washout period if they had abnormal serum aminotransferase (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) levels and detectable serum HCV-RNA by reverse transcription-polymerase chain reaction (RT-PCR) as previously described.3 Nineteen patients (49%) were previously treated in the context of the multicenter controlled trial of IFN-2b at the dose of 3 MU thrice weekly3 and the remaining 20 were patients with similar features who had received 3 MU of IFN-2a or IFN-2b outside the trial (Table 1).                                View this table: [in this window] [in a new window]   Table 1. Characteristics of the 39 patients at study entry Each patient received 5 MU recombinant IFN-2b (Intron A, Schering-Plough, Milan, Italy) by subcutaneous injections thrice weekly for 6 months followed by 3 MU thrice weekly for 6 additional months. An oral dose of 1000 to 1200 mg ribavirin (1200 mg if body weight was above 75 kg; Rebetol, Schering-Plough) was given daily for 12 months. Combination therapy was interrupted if a biochemical and virologic response was not achieved after the first 6 months or a permanent breakthrough occurred. Pretreatment serum levels of HCV-RNA were quantitatively measured by a branched-DNA signal amplification assay (bDNA, Quantiplex, HCV-RNA 2.0 assay; Chiron, Emeryville, CA; sensitivity threshold of this assay is 0.2 mEq/mL15). HCV was typed by an hybridization assay (Inno-Lipa II, Innogenetics, Zwijndrecht, Belgium). Serum HCV-RNA was assessed by nested RT-PCR, using specific primers from the 5' noncoding region with a limit sensitivity of 50 copies/mL.16 Continuous variables were expressed as mean or median values and ranges. Categorical variables were expressed as frequency and percent values and compared by the Fisher exact test. The Wilcoxon rank sum test was used to analyze the distribution of quantitative variables of the relevant clinicopathologic parameters. The median values were compared by the median test for 2 samples. All comparisons were 2-tailed. Response to treatment was evaluated in accordance with the intention-to-treat analysis. Univariate analysis was performed with each variable to assess any association with response to treatment.     Results and discussion Top Abstract Introduction Study design Results and discussion Appendix References All but one patient who refused to continue therapy at month 2 completed the study. Twenty-seven patients (69%) became HCV-RNA negative during the first 6 months of therapy and were continued on combination therapy until month 12. One responder, however, discontinued treatment at month 6 because of the occurrence of side effects. Five (19%) patients experienced a hepatitis breakthrough 6 to 11 months after starting therapy. At the end of treatment, 18 (46%) patients had normal ALT values and no HCV-RNA. Hepatitis relapse occurred in 4 end-of-treatment responders during the posttreatment follow-up period. Overall, 14 patients (36%) had a sustained response. In nonhemophilic patients with chronic hepatitis C, retreatment of transient responders to IFN monotherapy with IFN plus ribavirin was associated with a high rate (49%) of sustained virologic response.17 Relatively high rates (30%) of sustained virologic responses to retreatment with combination therapy of nonhemophilic patients who failed to respond to IFN monotherapy, including those infected by genotype 1, have been recently reported.13,18 In this study, we were surprised to see that retreatment with combination therapy led to a sustained virologic response not only in the 7 (47%) hemophilic patients who transiently responded to IFN monotherapy, but also in the 7 (29%) hemophilic patients who were primary nonresponders to IFN monotherapy. One possible explanation for these favorable results might be the use of relatively high doses of IFN, that is, 5 MU in the initial 6 months of therapy, which is known to overcome resistance of HCV infection to the first course of treatment with standard doses of 3 MU IFN.19 In both our study and that performed in the United States in nonhemophilic nonresponders,13 HCV genotype 1 was a strong predictor of nonresponse to retreatment with combination therapy. These findings parallel previous data showing that genotype 1 is an independent predictor of resistance to combination therapy in both naive and relapsed patients. The serum ALT level became normal at month 1 (86%) in 12 sustained responders compared to 1 (25%) patient with a posttreatment relapse. At variance with previous studies20,21 we found that high pretreatment serum ALT levels predicted a therapeutic response (Table 2).                                View this table: [in this window] [in a new window]   Table 2. Pretreatment characteristics of the patients who had a sustained response and those without sustained response to combination therapy Treatment was generally well tolerated by most patients, but it had to be discontinued in 4 (10%) because of the occurrence of side effects such as fatigue, anorexia, and nausea. Reduction of IFN dosage was required in 4 patients (10%) because of onset of fatigue, thrombocytopenia, and hypothyroidism. Ribavirin reduction was required in 6 patients (16%) because of the occurrence of hemolytic anemia 1 to 3 months after treatment onset. In all patients, hemoglobin levels transiently decreased during treatment (median variation from baseline, 2.9 g/dL; range, 0.2-5.2 g/dL). The 10% dropout rate caused by unwanted effects compares favorably with the figures of treatment toxicity reported by the megatrials in nonhemophilic patients.7,8,17 In conclusion, our finding that one third of nonresponders eventually achieved a sustained response with retreatment by combination therapy may have an important clinical impact, because chronic hepatitis C is a major cause of morbidity and mortality from liver disease in HIV-free hemophilic patients.1,22 The relevance of our findings lies also in the fact that hemophilic patients not responding to IFN monotherapy represent more than two thirds of all treated patients3,5,23 and that health-related quality of life, markedly impaired in patients with chronic hepatitis C, is expected to improve in those who respond to IFN treatment.24,25     Acknowledgments We thank Dr Antonio Russo, Department of Epidemiology, Local Health Authority of Milan, for his help in statistical analysis.     Footnotes Submitted July 27, 2001; accepted September 27, 2001. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Massimo Colombo, Division of Hepatology, IRCCS Maggiore Hospital, Via Pace 9, 20122 Milan, Italy; e-mail massimo.colombo{at}unimi.it.     References Top Abstract Introduction Study design Results and discussion Appendix References 1. Darby SC, Ewart DW, Giangrande PLF, et al. Mortality from liver cancer and liver disease in haemophilic men and boys given blood products contaminated with hepatitis C. Lancet. 1997;350:1425-1431[CrossRef][Medline] [Order article via Infotrieve]. 2. Makris M, Preston FE, Rosendaal FR, Underwood JCE, Rice KM, Triger DR. The natural history of chronic hepatitis C in hemophiliacs. Blood. 1996;94:746-752. 3. Rumi MG, Santagostino E, Morfini M, et al. A multicenter controlled, randomized, open trial of interferon 2b treatment of anti-human immunodeficiency virus-negative hemophilic patients with chronic hepatitis C. Blood. 1997;89:3529-3533[Abstract/Free Full Text]. 4. Telfer P, Devereux H, Colvin B, Hayden S, Dusheiko G, Lee C. Alpha interferon for hepatitis C virus infection in haemophilic patients. Haemophilia. 1995;1:54-58. 5. Hanley JP, Jarvis LM, Andrews J, et al. Interferon treatment for chronic hepatitis C infections in hemophiliacs. Influence of virus load genotype and liver pathology on response. Blood. 1996;87:1704-1709[Abstract/Free Full Text]. 6. Pawlotsky JM, Roudot-Thoraval F, Bastie A, et al. Factors affecting treatment responses to interferon  in chronic hepatitis C. J Infect Dis. 1996;174:1-7[Medline] [Order article via Infotrieve]. 7. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339:1485-1492[Abstract/Free Full Text]. 8. Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426-1432[CrossRef][Medline] [Order article via Infotrieve]. 9. Lohmann V, Korner F, Herian U, Bartenschlager R. Biochemical properties of hepatitis C NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J Virol. 1997;71:8416-8428[Abstract]. 10. Crotty S, Maag D, Arnold JJ, et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat Med. 2000;6:1375-1379[CrossRef][Medline] [Order article via Infotrieve]. 11. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci U S A. 2001;98:6895-6900[Abstract/Free Full Text]. 12. Hultgren C, Milich DR, Weiland O, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol. 1998;79:2381-2391[Abstract]. 13. Cramp ME, Rossol S, Chokshi S, Carucci P, Williams R, Naoumov NV. Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C. Gastroenterology. 2000;118:346-355[CrossRef][Medline] [Order article via Infotrieve]. 14. Di Bisceglie AM, Thompson J, Smith-Wilkaitis, Brunt EM, Bacon BR. Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon. Hepatology. 2001;33:704-707[CrossRef][Medline] [Order article via Infotrieve]. 15. Detmer J, Lagier R, Flynn J, et al. Accurate quantification of HCV-RNA from all HCV genotypes using branched-DNA (bDNA) technology. J Clin Microbiol. 1996;34:901-907[Abstract]. 16. Rumi MG, Del Ninno E, Parravicini ML, et al. Long-term titrated recombinant interferon- 2a in chronic hepatitis C: a randomized controlled trial. J Viral Hepat. 1995;2:73-76[Medline] [Order article via Infotrieve]. 17. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med. 1998;339:1493-1499[Abstract/Free Full Text]. 18. Cheng SJ, Bonis PAL, Lau J, Pham NQ, Wong JB. Interferon and ribavirin for patients with chronic hepatitis C who did not respond to previous interferon therapy: a meta-analysis of controlled and uncontrolled trials. Hepatology. 2001;33:231-240[CrossRef][Medline] [Order article via Infotrieve]. 19. Saracco G, Ciancio A, Olivero A, et al. A randomized 4-arm multicenter study of interferon -2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon alone. Hepatology. 2001;34:133-138[CrossRef][Medline] [Order article via Infotrieve]. 20. Davis GL, Lau JYN. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology. 1997;26(suppl 1):122-127[CrossRef]. 21. Rumi MG, Del Ninno E, Parravicini ML, et al. A prospective randomized trial comparing lymphoblastoid to recombinant interferon alfa 2a as therapy for chronic hepatitis C. Hepatology. 1996;24:1366-1370[CrossRef][Medline] [Order article via Infotrieve]. 22. Troisi CL, Hollinger FB, Hoots WK, et al. A multicenter study of viral hepatitis in a United States hemophilic population. Blood. 1993;81:412-418[Abstract/Free Full Text]. 23. Pinilla J, Quintana M, Magallon M. High-dose and long-term treatment of  interferon in hemophilic patients with chronic C virus hepatitis. Blood. 1998;91:727-728[Free Full Text]. 24. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology. 1998;27:209-212[CrossRef][Medline] [Order article via Infotrieve]. 25. Bonkovsky HL, Woolley JM. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. Hepatology. 1999;29:264-270[CrossRef][Medline] [Order article via Infotrieve].     Appendix Top Abstract Introduction Study design Results and discussion Appendix References The following colleagues participated in this study by the Hepatitis Study Group of the Association of Italian Hemophilia Centers: M. Morfini, Department of Hematology and Hemophilia Center, Careggi Hospital, Florence; G. Tagariello, Hemophilia Center, Castelfranco Veneto Hospital, Treviso; M. G. Mazzucconi, Department of Hematology, La Sapienza University, Rome; F. Baudo, Department of Hematology and Hemophilia Center, Niguarda Hospital, Milan; G. Muleo, Department of Hematology and Hemophilia Center, Pugliese Hospital,Catanzaro; A. Rocino, Department of Hematology and Hemophilia Center, S. Giovanni Bosco Hospital, Naples; G. Rossetti, Hemophilia Center, S. Chiara Hospital, Trento; and L. Tasso (deceased), Division of Infectious Diseases, G. Gaslini Hospital, Genoa. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Franchini, C. Mengoli, D. Veneri, R. Mazzi, G. Lippi, and M. Cruciani Treatment of chronic hepatitis C in haemophilic patients with interferon and ribavirin: a meta-analysis J. Antimicrob. Chemother., June 1, 2008; 61(6): 1191 - 1200. [Abstract] [Full Text] [PDF] T. Honda, H. Toyoda, K. Hayashi, Y. Katano, M. Yano, I. Nakano, K. Yoshioka, H. Goto, K. Yamamoto, and J. Takamatsu Ribavirin and Use of Clotting Factors in Patients With Hemophilia and Chronic Hepatitis C JAMA, March 9, 2005; 293(10): 1190 - 1192. [Full Text] [PDF] P. M. Mannucci Ham-Wasserman Lecture : Hemophilia and Related Bleeding Disorders: A Story of Dismay and Success Hematology, January 1, 2002; 2002(1): 1 - 9. [Abstract] [Full Text] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Santagostino, E. Articles by Mannucci, P. M. Search for Related Content PubMed PubMed Citation Articles by Santagostino, E. Articles by Mannucci, P. M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020